Although some forms of dementia can be treated (i.e., dementias resulting from cardiovascular disease, chemical toxins, depression, or head trauma) no effective therapy currently exists for the major form of dementia, senile dementia of the Alzheimer's type (SDAT), which accounts for more than half of all dementias, Moos et al., Med. Res. Reviews 8 (3), 353 (1988). The reason for this is that the etiology of the disease has not yet been confirmed, though many theories exist, Henderson, Acta Psychiat. Scand. 78, 257 (1988); Marx, Science 243, 1664 (1989). One theory which has gained wide acceptance is that the cognitive decline observed in patients with Alzheimer's disease and other forms of dementia is related to hypofunction of the cholinergic system, Bartus et al., Science 217, 408 (1982): Collerton, Neuroscience 19 (1), 1 (1986) and Whitehouse et al., Ann. Neurol., 10, 122 (1981). A study comparing patients with Alzheimer's disease (50), other dementias (10), and age-matched controls (20) found that 50-76% of the Alzheimer's patients had a statistically significant loss of cholinergic neurons in the basal forebrain. Other studies have revealed that loss of presynaptic cholinergic neurons in the amygdala, hippocampus and neocortex related to hypofunction of the basal forebrain cholinergic system is also found in Parkinson's disease, Down's syndrome, dementia pugelistica, and some other forms of dementia, Whitehouse et al., Adv. Behav. Biology 29, 85 (1985).
The neurotransmitter of the cholinergic system in acetylcholine. Receptor binding studies on brain tissue from animals (e.g. rats) and humans have identified two major types of acetylcholine (muscarinic) receptors, presynaptic receptors on nerve terminals (M.sub.2) and postsynaptic receptors (M.sub.1). Postmortem examination of brain tissue from Alzheimer's patients has shown that while postsynaptic M.sub.1 receptors remain intact, there is a reduction in the number of presynaptic M.sub.2 receptors, Marx, ibid. In fact, there is good correlation between the degree of presynaptic neuronal loss and the severity of the dementia, Marx, ibid, Collerton, ibid.
Degeneration of presynaptic cholinergic neurons results in insufficient production of acetylcholine and understimulated postsynaptic M.sub.1 receptors. Memory loss in normal humans, Bartus et al., ibid and Drachman et al., Arch. Neurol. 30, 113 (1974) and animals (e.g. cat, rat, and monkey), Bartus et al., ibid and Collerton, ibid can be artificially induced with a muscarinic antagonist, such as scopolamine. This deficit can be reversed by the anticholinesterase inhibitor, physostigmine; in both humans and monkeys, Marx, ibid and by the muscarinic agonist arecoline in rats. However, neither physostigmine nor arecoline have clinical efficacy due to undesirable side-effects, a short duration of action and a narrow active dose range. Other therapies examined in clinical studies include treatment of Alzheimer's patients and healthy elderly patients with the acetylcholine precursors choline and lecithin. No significant improvement was observed on any cognitive test.
Over the next 50 years it is predicted that nearly 20% (55 million) of the population in the United States will be over 65 years of age, Moos et al., ibid. Couple this with the fact that Alzheimer's disease alone afflicts between 5 and 15% of individuals over 65 years of age, Collerton, ibid and it becomes obvious that dementia is a major health problem for which there is an urgent need for effective therapy. Centrally acting compounds which have greater affinity for the M.sub.1 receptor than the M.sub.2 receptor as evidenced by in vitro receptor binding studies may be useful for the treatment of Alzheimer's disease and other disorders associated with cortical cholinergic hypofunction. M.sub.1 receptor selective compounds are expected to have fewer undesirable side effects than those which are not M.sub.1 selective since unwanted peripheral effects are usually associated with the M.sub.2 receptor.